Modeling the growth dynamics of multiple Escherichia coli strains in the pig intestine following intramuscular ampicillin treatment.

Amais Ahmad,Kaare Græsbøll,Louise Matthews,Nils Toft,Camilla Zachariasen,Søren Saxmose Nielsen,Lasse Engbo Christiansen,John Elmerdahl Olsen

doi:10.1186/s12866-016-0823-3

Abstract

BackgroundThis study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs. It also examined the dynamics of the composition of bacterial strains during and after the treatment. The growth responses of strains to ampicillin concentrations were determined using in vitro growth curves. Using these results as input data, growth predictions were generated using a mathematical model to simulate the competitive growth of E. coli strains in a pig intestine under specified plasma concentration profiles of ampicillin.ResultsIn vitro growth results demonstrated that the resistant strains did not carry a fitness cost for their resistance, and that the most susceptible strains were more affected by increasing concentrations of antibiotics that the rest of the strains. The modeling revealed that short treatment duration resulted in lower levels of resistance and that dosing frequency did not substantially influence the growth of resistant strains. Resistance levels were found to be sensitive to the number of competing strains, and this effect was enhanced by longer duration of treatment. High excretion of bacteria from the intestine favored resistant strains over sensitive strains, but at the same time it resulted in a faster return to pre-treatment levels after the treatment ended. When the duration of high excretion was set to be limited to the treatment time (i.e. the treatment was assumed to result in a cure of diarrhea) resistant strains required longer time to reach the previous level.ConclusionNo fitness cost was found to be associated with ampicillin resistance in E. coli. Besides dosing factors, epidemiological factors (such as number of competing strains and bacterial excretion) influenced resistance development and need to be considered further in relation to optimal treatment strategies. The modeling approach used in the study is generic, and could be used for prediction of the effect of treatment with other drugs and other administration routes for effect on resistance development in the intestine of pigs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-016-0823-3) contains supplementary material, which is available to authorized users.

Highlights

This study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs
The study comprised three steps: 1) estimation of pharmacodynamic parameters of a representative collection of porcine E. coli strains based on in vitro growth experiments, 2) estimation of concentration-time profiles of ampicillin following IM treatment, based on literature data, and 3) predictions of the competitive growth of multiple E. coli strains with varying duration and frequency of IM ampicillin treatment and with varying excretion rates of bacteria from the intestine, corresponding to the effect of diarrhea
A relationship between ampicillin concentrations and net bacterial growth rates was obtained for each strain, and an Emax model was fitted to this relationship based on three PD parameters

Summary

Introduction

This study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs. It examined the dynamics of the composition of bacterial strains during and after the treatment. This disturbance may create large pools of resistant bacteria that could lead to a general increase and spread of antimicrobial resistance [2]. The major organ of concern is the intestine, since it contains the highest number of bacteria at risk, and confers a means of direct transfer of resistant bacteria via feces

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